NHLBI CLINICAL INVESTIGATOR AWARD

长期以来，我一直致力于学术研究， 事业 我的研究经验主要集中在珠蛋白基因调控 而我的医学背景包括4年的强化临床训练 内科学和血液学 本方案拟开发的领域 包括基本科学知识、确定研究重点能力 评估可行性，获得资金和管理实验室的能力， 能够严格解决特定临床重要问题。 染色质结构是研究珠蛋白临床问题的一种方法 镰状细胞病和β地中海贫血的调节。 许多当前 技术不适合高等生物。 酵母提供了一种 替代的，基因操纵的，系统，可以探索，而新的 开发了哺乳动物系统的方法。 一项新技术，2 染色质的三维杂交图谱将用于检测 重要的结构酵母蛋白，如HMG和序列特异性 结合蛋白 受调节的基因将在活性和 以Tyl重复元件开始并进展到 单拷贝基因 调节突变体、回复突变体和生长缺陷型 (CDC)将研究突变体。 限制性内切酶消化 将探索染色质。 最终这些技术将被用于 与哺乳动物系统中的珠蛋白调节有关。 研究进展 技能将分为三个阶段。 第一个是紧张的基础科学 在麻省理工学院瓦沙夫斯基博士的实验室里的经历。 我会集中讨论 设计和执行实验，写论文，扩大我的 科学基础。 临床联系将通过每周一次 诊所涉及不到10%的努力。 第二阶段将是 从监督工作向独立工作过渡。 所述相互作用与 Varshavsky博士和Nathan博士都应该帮助平衡临床应用 和科学严谨性。 最后阶段是作为独立调查员 探索哺乳动物胎儿到成人的珠蛋白转换， 染色质技术

I have long had a deep and consistent commitment to an academic research career. My research experience has concentrated on globin gene regulation while my medical background includes 4 years of intensive clinical training in internal medicine and hematology. Areas to be developed by this program include basic science knowledge, ability to set research priorities and assess feasibility, ability to obtain funding and administer a lab and the ability to rigorously address questions of specific clinical import. Chromatin structure is one approach to the clinical problem of globin regulation in sickle cell disease and beta thalassemia. Many current techniques are not suitable for higher organisms. Yeast offers an altenative, genetically manipulable, system that can be explored while new approaches to the mammalian system are developed. A new technique, two dimensional hybridization mapping of chromatin will be used to detect important structural yeast proteins, such as HMGs and sequence specific binding proteins. Regulated genes will be studied in both active and inactive forms beginning with the Tyl repetative element and progressing to single copy genes. Regulation mutants, revertants and growth defective (CDC) mutants will be studied. Restriction endonuclease digestion of chromatin will be explored. Eventually these techniques will be brought to bear on globin regulation in mammalian systems. Development of research skills will be in 3 phases. The first is an intense basic science experience in the lab of Dr. Varshavsky at MIT. I will concentrate on designing and performing experiments, writing papers and broadening my scientific base. Clinical contact will be maintained through a weekly clinic involving less than 10% effort. The second phase will be a transition from supervised work toward independence. The interaction with both Drs. Varshavsky and Nathan should help balance clinical applications and scientific rigor. The final phase is as an independent investigator exploring the mammalian fetal to adult globin switch with rigorous chromatin technology.